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Retinal Vessel Analysis: Flicker Reproducibility, Methodological Standardisations and Practical Limitations

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Retinal Vessel Analysis: Flicker Reproducibility, Methodological Standardisations and Practical Limitations Some pages of this thesis may have been removed for copyright restrictions. If you have discovered material in AURA which is unlawful e.g. breaches copyright, (either yours or that of a third party) or any other law, including but not limited to those relating to patent, trademark, confidentiality, data protection, obscenity, defamation, libel, then please read our Takedown Policy and contact the service immediately RETINAL VESSEL ANALYSIS: FLICKER REPRODUCIBILITY, METHODOLOGICAL STANDARDISATIONS AND PRACTICAL LIMITATIONS ANGELOS KALITZEOS Doctor of Philosophy ASTON UNIVERSITY September ©Angelos Kalitzeos, Angelos Kalitzeos asserts his moral right to be identified as the author of this thesis is copy of the thesis has been supplied on condition that anyone who consults it is understood to recognise that its copyright rests with its author and that no quotation from the thesis and no information derived from it may be published without proper acknowledgement. Aston University Retinal Vessel Analysis: Flicker Reproducibility, Methodological Standardisations and Practical Limitations Angelos Kalitzeos Doctor of Philosophy esis Summary: e Retinal Vessel Analyser (RVA) is a commercially available ophthalmoscopic instrument capable of acquiring vessel diameter fluctuations in real time and in high temporal resolution. Visual stimulation by means of flickering light is a unique exploration tool of neurovascular coupling in the human retina. Vessel reactivity as mediated by local vascular endothelial vasodilators and vasoconstrictors can be assessed non-invasively, in vivo. In brief, the work in this thesis • deals with interobserver and intraobserver reproducibility of the flicker responses in healthy volunteers • explains the superiority of individually analysed reactivity parameters over vendor- generated output • links in static retinal measures with dynamic ones • highlights practical limitations in the use of the RVA that may undermine its clinical usefulness • provides recommendations for standardising measurements in terms of vessel location and vessel segment length and • presents three case reports of essential hypertensives in a -year follow-up. Strict standardisation of measurement procedures is a necessity when utilising the RVA system. Agreement between research groups on implemented protocols needs to be met, before it could be considered a clinically useful tool in detecting or predicting microvascular dysfunction. Keywords: Cardiovascular Disease, Autoregulation, Blood Pressure, Endothelial Function Contents List of Figures 7 List of Tables 9 1 Overview of principal literature 11 . e Heart ....................................... .. Cardiac Anatomy and Physiology ..................... .. Conduction System ............................. . Cardiovascular System ............................... .. Blood Flow ................................. .. Arterial Blood Pressure ........................... .. Regulation of Blood Pressure ....................... ... Mean Arterial Blood Pressure and Pulse Pressure ...... . Diagnostic Tests and Procedures .......................... .. Ambulatory BP Monitoring ........................ ... Ambulatory Arterial Stiffness Index .............. .. Electrocardiography ............................ ... Ambulatory ECG Monitoring ................. ... Heart Rate Variability ...................... .. CardioTens -hour ECG and BP monitoring .............. . Hypertension .................................... .. Definition and Classification of Hypertension .............. .. Management of Hypertension ....................... . Peripheral Circulation ................................ . e Eye ........................................ .. Retinal Vasculature ............................. .. Posterior Eye Haemodynamics ...................... . alitative Retinal Analysis ............................ .. e Keith-Wagener-Barker Classification ................. Contents . antitative Retinal Analysis ........................... .. Assessing Retinal Structure ........................ ... Arterio-Venous Ratio ...................... ... Vessel Tortuosity Index ..................... ... Bifurcation Angles and Junction Exponents .......... ... Length-to-Diameter Ratio ................... .. Assessing Retinal Vessel Dynamics .................... ... Retinal Vessel Analyser ..................... ... Flicker Provocation ....................... ... Dynamic Response Analysis .................. ... Other External Provocations .................. .. Retinal Oximetry .............................. .. Visual Field Testing ............................. . Nailfold Capillaroscopy ............................... .. Measurement Principle ........................... .. CapiScope Capillaroscopy System ..................... 2 Retinal Vessel Analyser: Reproducibility 43 . Background ..................................... .. Motivation and Research Rationale .................... .. Aims ..................................... . Subjects and Methods ................................ .. Interobserver Reproducibility ....................... .. Intraobserver Reproducibility ....................... .. Standardisations Applied .......................... .. Inclusion and Exclusion Criteria ...................... .. Study Protocol ............................... ... Intraocular Pressure Measurement ............... ... Blood Pressure and Pulse Assessment ............. ... Retinal Vessel Functional Assessment ............. ... Retinal Vessel Structural Assessment ............. .. Outcome Measures ............................. .. Dynamic Parameters ............................ .. Static Parameters .............................. .. Statistics and Data Analysis ........................ Contents . Results ........................................ .. Interobserver Reproducibility ....................... ... Subjects ............................. ... Retinal Vessels’ Absolute Diameters .............. ... Inbuilt Dynamic Flicker Response Analysis .......... ... Independent Dynamic Flicker Response Analysis ...... ... Comparison Between Inbuilt and Independent Analysis ... ... Averaged Flicker Responses .................. .. Intraobserver Reproducibility ....................... ... Subjects ............................. ... Retinal Absolute Diameters ................... ... Inbuilt Dynamic Flicker Response Analysis .......... ... Independent Dynamic Flicker Response Analysis ...... ... Comparison Between Inbuilt and Independent Analysis ... ... Averaged Flicker Responses .................. ... Static Retinal Vessel Parameters ................ ... Multiple Regression Analysis .................. . Discussion ...................................... .. Interobserver Reproducibility Study ................... .. Intraobserver Reproducibility Study ................... . Conclusions ..................................... 3 Location and Length Influence on Vessel Reactivity 73 . Background ..................................... .. Motivation and Research Rationale .................... . Subjects and Methods ................................ .. Data Collection ............................... .. Data Processing ............................... ... Analysis per Location ...................... ... Analysis per Segment’s Length ................ .. Data and Statistical Analysis ........................ . Results ........................................ .. Baseline Characteristics .......................... .. Comparison Across Vessel Segments ................... .. Flicker Responses Variability as a Function of Location ......... .. Comparison Between Segment Lengths ................. Contents . Discussion ...................................... .. Measurement Location Considerations .................. .. Measurement Length Considerations ................... . Conclusions ..................................... 4 Essential Hypertension: Case Reports 92 . Introduction and Motivation ............................ . Ethical Approval ................................... . Methods and Subjects ................................ .. Day - Ambulatory BP and ECG Monitoring .............. ... Outcome Measures ....................... .. Day - Eye examinations ......................... ... Intraocular Pressure Measurement ............... ... Retinal Functional Analysis .................. ... Outcome Measures ....................... .. Data Analysis ................................ . Results ........................................ .. Sample .................................... .. hr BP and ECG Monitoring ....................... .. Retinal Functional Assessment ...................... . Discussion ...................................... Bibliography 99 Acronyms 114 Appendix 116 List of Figures . Primary physiologic factors affecting certain physical factors. ......... . Graphical representation of the blood pressure wave. .............. . Two complete, normal ECG cycles. ........................ . Modified three-electrode bipolar lead system. ................... . e time series of R-R intervals, i.e. tachogram. .................. . Power Spectral Density of the tachogram in Figure .. ............. . Set-up window of the CardioVisions soware. .................. . Normal fundus image of a le eye, ONH centered, °. .............. . Normal fundus image of a right eye, macula centered, °. ............ . Concentric AVR measurement rings as defined by the ARIC study. ....... . Schematic
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